MicroRNAs, inflammation, and acute lung injury.

MicroRNA、炎症和急性肺损伤。

• 批准号: 7990182
• 负责人: Gang Liu
• 金额: $ 18.31万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990182
• 关键词: Acute; Acute Lung Injury; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Binding; Cardiovascular Diseases; Cells; Data; Development; Diabetes Mellitus; Disease; Distant; Equilibrium; Event; Functional RNA; Functional disorder; Gene Expression; Goals; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Invaded; Life; Liver; Lung; Malignant Neoplasms; Mediator of activation protein; MicroRNAs; Mus; Nucleotides; Organ; Outcome; Pathogenesis; Play; Population; Property; Reactive Oxygen Species; Regulation; Regulator Genes; Role; Severities; Small RNA; Subfamily lentivirinae; TLR4 gene; Therapeutic; Up-Regulation; Virus Diseases; chemokine; cytokine; improved; in vivo; intravenous administration; lung injury; macrophage; microorganism; monocyte; neutrophil; novel therapeutic intervention; prevent; promoter; public health relevance; response

DESCRIPTION (provided by applicant): MicroRNAs, a class of 21-22 nucleotide non-coding small RNAs, are important regulators of gene expression and have been shown to modulate a broad range of cellular and developmental events. We have found that the expression of miR147 is upregulated in LPS stimulated cells and miR147 has anti-inflammatory properties which diminish activation in macrophages. Our data therefore suggest that specific microRNAs participate in regulating acute TLR4 induced inflammatory events and that modulation of microRNAs may have potential therapeutic benefit in life-threatening inflammatory conditions, such as ALI. Our hypothesis is that miR147 participates in the regulation of acute inflammatory responses and play a major role in determining the development, perpetuation, and severity of ALI. Our specific aims are: 1) To characterize the role of miR147 in regulating TLR4 induced inflammatory responses by delineating the mechanisms leading to LPS induced upregulation in the expression of miR147, elucidating the role that miR147 occupies in modulating LPS induced cellular activation, and delineating the mechanisms through which miR147 affects LPS induced cellular activation. 2) To explore if modulation of the expression of miR147 attenuates LPS induced ALI by determining the expression of miR147 in the lungs of LPS treated mice and exploring if modulation of miR147 expression can attenuate LPS induced ALI. The proposed studies should not only improve understanding of cellular mechanisms leading to ALI, but also are likely to suggest novel therapeutic interventions aimed at decreasing the incidence and/or severity of ALI. PUBLIC HEALTH RELEVANCE: MicroRNAs are important regulators of many essential cellular and developmental events. Deregulations of microRNA expression have been shown to be involved in a number of diseases, such as cancer, cardiovascular diseases, and diabetes. However, whether microRNAs regulate acute inflammatory responses and acute inflammation related diseases, including acute lung injury (ALI) has not been elucidated. We found that the expression of miR147 is upregulated in LPS stimulated macrophages and mouse lungs and miR147 has anti-inflammatory activities. The studies proposed in this application should not only improve understanding of the roles of microRNAs in regulation of LPS induced inflammatory responses and acute lung injury, but also are likely to suggest novel therapeutic interventions aimed at decreasing the incidence and/or severity of acute lung injury.

描述（由申请人提供）：MicroRNA 是一类 21-22 核苷酸非编码小 RNA，是基因表达的重要调节因子，并且已被证明可以调节广泛的细胞和发育事件。我们发现 miR147 的表达在 LPS 刺激的细胞中上调，并且 miR147 具有抗炎特性，可减少巨噬细胞的活化。因此，我们的数据表明，特定的 microRNA 参与调节 TLR4 诱导的急性炎症事件，并且 microRNA 的调节可能对危及生命的炎症状况（例如 ALI）具有潜在的治疗益处。我们的假设是 miR147 参与急性炎症反应的调节，并在确定 ALI 的发展、持续和严重程度方面发挥重要作用。我们的具体目标是：1）通过描述导致LPS诱导的miR147表达上调的机制来表征miR147在调节TLR4诱导的炎症反应中的作用，阐明miR147在调节LPS诱导的细胞激活中的作用，并描述miR147影响LPS诱导的细胞激活的机制。 2)通过测定LPS治疗小鼠肺中miR147的表达，探讨miR147表达的调节是否可以减弱LPS诱导的ALI，并探索miR147表达的调节是否可以减弱LPS诱导的ALI。拟议的研究不仅应该增进对导致 ALI 的细胞机制的理解，而且还可能提出旨在降低 ALI 发生率和/或严重程度的新治疗干预措施。 公共卫生相关性：MicroRNA 是许多重要细胞和发育事件的重要调节因子。 microRNA 表达失调已被证明与许多疾病有关，例如癌症、心血管疾病和糖尿病。然而，microRNA是否调节急性炎症反应和急性炎症相关疾病，包括急性肺损伤（ALI）尚未阐明。我们发现 miR147 的表达在 LPS 刺激的巨噬细胞和小鼠肺部中上调，并且 miR147 具有抗炎活性。本申请中提出的研究不仅应该提高对 microRNA 在调节 LPS 诱导的炎症反应和急性肺损伤中的作用的理解，而且还可能提出旨在降低急性肺损伤的发生率和/或严重程度的新的治疗干预措施。